Melanoma from the dermatologist's perspective

Facial Plast Surg Clin N Am 11 (2003) 277 – 286

Melanoma from the dermatologist’s perspective Ashley A. Smith, BAa, Amy B. Cole, MDb,*, Scott W. Fosko, MDb b

a St. Louis University, 4961 Laclede Avenue, Suite 601, St. Louis, MO 63108, USA Department of Dermatology, St. Louis University, 1402 Grand Boulevard, St. Louis, MO 63104, USA

Every physician should have a strong working knowledge of melanoma. The incidence of melanoma is increasing at a greater rate than that of any other cancer [1 – 7]. Melanoma is the most deadly form of skin cancer, accounting for more than six of every seven deaths caused by cutaneous malignancies [9,10]. Melanoma of the head and neck region is common, and it is important that physicians who deal with this area remain up to date on the diagnosis, staging, and treatment of this increasingly common malignancy. This article provides an overview of malignant melanoma, a description of diagnostic features, a discussion of biopsy technique, and a brief synopsis of staging and treatment.

Incidence In recent decades, the incidence of melanoma in fair-skinned Caucasian individuals has increased by 3% to 7% per year [7]. The cumulative lifetime risk for Americans is approximately 1/75 [5,11,12], compared with the risk in 1960, when only 1/1500 persons was expected to develop this pathology. Once diagnosed with melanoma, the chance of developing a second primary melanoma is estimated to be between 1% and 8% [13]. Overall, melanoma ranks as the sixth most common cancer among men and the seventh most common cancer among women [14]. Melanoma rates are highest in Caucasians; they are substantially lower in Asians, Hispanics, and African Americans [8]. It is a disease of the relatively young; the median age of diagnosis is 45 years [15]. An

* Corresponding author.

estimated 25% to 30% of all melanomas are found within the head and neck region [16].

Mortality and survival Currently, melanoma accounts for 1% to 2% of all cancer deaths [14,17]. The 5-year survival rate has increased from 80% to 88% over the last two decades [18]. This increase in survival might be attributed in part to educational programs that have been in place for decades in the United States, Europe, Australia, and Asia [7]. These programs have led to increased detection of melanomas at an earlier stage. Given the steady climb in incidence of melanoma, however, the overall mortality rate continues to increase at a rate of 2% per year [7,12,19]. From 1973 to 1995, mortality caused by cutaneous melanoma rose 32.7%, as documented by the Surveillance, Epidemiology, and End Results Program (SEER) [20].

Risk factors Risk factors associated with melanoma include fair skin type and tendency toward sunburn or freckling [1,21 – 24]. Blue eyes and red or blonde hair might increase the risk as well [7,25]. Family history is an important factor; approximately 2% to 5% of melanomas might be familial in nature [26]. A positive family history of at least two first-degree relatives with melanoma portends an especially high risk. Patients with multiple atypical nevi (formerly called dysplastic nevi) have an increased risk of melanoma, perhaps as much as seven-fold (Fig. 1)

1064-7406/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved. doi:10.1016/S1064-7406(02)00047-0

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Fig. 1. Patient with multiple atypical or dysplastic nevi.

[6,27]. In patients with multiple atypical nevi and a family history of atypical nevi and melanoma, the incidence of melanoma approaches 100% [28]. Debate exists regarding whether or not the presence of a single atypical nevus increases one’s cancer risk [6]. As with many other cancers, the risk of melanoma increases with age. Although cases are reported in childhood, melanomas rarely develop before adolescence. Incidence begins to climb at approximately 20 years of age and continues to increase with advancing age [7]. It is difficult to assess if this increase is because of inherent age-related factors or simply to greater cumulative sun exposure [9]. Sunlight is the primary environmental factor associated with an increased risk of melanoma. In several epidemiologic studies, a history of childhood sunburns has shown to be an important risk factor [29]. The number of sunburns over one’s lifetime also appears to relate proportionally to melanoma risk [30]. This risk is higher in those who live closest to the equator [31,32]. Sunlight exposure can induce carcinogenicity by way of insults to DNA within skin cells. Ultraviolet radiation causes production of oxygen free radicals, which lead to DNA damage. This process of DNA

damage and subsequent repair might lead to DNA mutation and eventual malignant transformation. Ultraviolet radiation can be categorized by spectrum as ultraviolet A (UVA; 320 – 400 nm), which is linked to age-related changes such as actinic damage and rhytides, or ultraviolet B (UVB; 280 – 320 nm), which is the primary cause of sunburn. Although UVB radiation has traditionally been considered to be the primary damaging element in sunlight, it is now thought that both UVA and UVB radiation contribute to melanoma risk [33]. It has been proven that patients undergoing UVA exposure following administration of psoralen (PUVA treatment) are at increased risk of developing melanoma [34]. It has not been established whether or not radiation utilized in tanning beds and lamps (which employ predominately UVA radiation) poses as high a risk for melanoma as sunlight, but early studies demonstrate a clear association [35,36]. Controversy also exists over the pattern of sun exposure that is most likely to cause melanoma. Exposure to intense sunlight for brief periods and to lower levels absorbed on a chronic, daily basis are likely to contribute to melanoma risk [37]. Specific subtypes of melanoma might develop based upon these different sunlight exposure patterns. For example, lentigo malignas tend to present on the face, head, neck, and dorsal hands, which are locales associated with long-term, daily sun exposure [7,8].

Prognostic factors Established prognostic factors for melanoma include the Breslow’s depth, Clark’s level, tumor ulceration, tumor location, and patient gender [8,26,38 – 42]. The most important prognostic factor is the Breslow’s depth of the primary tumor, which is defined microscopically as the thickness from the granular cell layer in the epidermis to the deepest malignant cell. The Clark’s level, which is defined as the extent of invasion through distant skin layers, appears to have modest prognostic value in areas of thinner tissue such as the ear or eyelid [26]. Independent of lesion thickness, histologic subtype does not appear to influence prognosis significantly [43 – 47]. Tumor ulceration is considered to be a sign of poor prognosis—so much so that as with Breslow’s depth, ulceration is considered to be a major staging criterion [27,48]. For reasons that remain unclear, tumors located on the head and neck—particularly the scalp—confer a poorer prognosis than tumors located on the extremities [43,49]. In addition, male gender portends a somewhat worse prognosis [7,26,41].

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Clinical examination and diagnosis Frequent skin examinations are critical to early diagnosis of melanoma. Patients should be educated regarding the importance of regular self-examinations and should be instructed to notify a physician if any new skin lesions appear or an existing lesion changes or grows. Annual examinations by a dermatologist are recommended for patients at high risk and individuals over 20 years of age. The most common signs used to distinguish melanomas from benign lesions are included in the ABCD mnemonic: asymmetry, border irregularity, color variability, and diameter greater than 6 mm. Other worrisome characteristics include tenderness, bleeding, enlargement, crusting, redness, and friability [10]. Pruritic lesions should be given special attention because itching is present in almost 50% of melanoma cases. Late signs, which confer a poorer prognosis, include ulceration and discomfort [6]. Adequate lighting is crucial for a good skin examination. While daylight is ideal, direct, bright lights and tangential lighting are helpful alternatives. A magnifying hand lens or loupes can be used to better visualize lesions [10]. Other useful tools in the clinical environment include a Wood’s lamp, dermatoscope, and camera. The Wood’s lamp is a hand-held black light that can help delineate the extent of irregularly bordered melanomas or locate leukoderma patches, which are associated with regressed melanomas [10]. The Wood’s lamp is particularly helpful in establishing the extent of lentigo malignas, often enhancing areas of involvement beyond those seen on clinical examination. Epiluminescence microscopy is a technique in which oil is applied to a pigmented lesion. The lesion is then examined through a dermatoscope, a hand-

Fig. 3. Atypical nevus.

held viewing device resembling an otoscope. This device greatly enhances lesion pigmentation, and in experienced hands it might improve diagnostic accuracy by 20% to 50% [10]. Epiluminescence microscopy has been especially popular in Europe. Sequential photographs, whole-body images, or images of particular nevi are an objective complement to a patient’s file. Photographs can be referenced at follow-up examinations and can be used by patients to aid with self-examinations. Total body photography is particularly useful for patients with atypical nevi or a history of melanoma.

Precursor lesions and melanoma subtypes Atypical (dysplastic) nevi can be characterized clinically by a diameter greater than 6 mm, irregular pigmentation, indistinct borders, or a textured surface. Some lesions have been described as having a ‘‘fried-egg’’ appearance because of the presence of a peripheral macular component surrounding a centrally raised papule (Figs. 2, 3) [50]. Histologically, these lesions do not show features of melanoma, but they might demonstrate architectural disorder with or without varying degrees of cytologic atypia. Superficial spreading melanoma

Fig. 2. Atypical nevus.

Superficial spreading melanoma is the most prevalent form of melanoma, comprising 80% of cases occurring in Caucasians [8,26]. These lesions frequently arise in pre-existing nevi. Clinically, these lesions appear as papules with variegated pigment, ranging from dark brown – black to gray – white (Figs. 4 – 6). In women, they occur most commonly on the lower extremities, whereas the upper back is the most common site in men. These tumors typically have an initial radial growth phase followed by a

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Fig. 4. Superficial spreading melanoma. Note the variegated color.

vertical growth phase that develops over a period of months to years. Nodular melanoma Nodular melanomas (NM) account for 5% to 15% of melanoma cases [8]. NMs often appear as uniform, darkly pigmented papules or nodules that are most commonly located on the head, neck, or trunk. They tend to present and progress quickly with early vertical growth. A small percentage of nodular melanomas lack pigment, appearing pink or skin-colored. These amelanotic lesions present a diagnostic challenge because they might not possess the worrisome features that are common to most melanomas. Lentigo maligna Lentigo maligna (LM) is a form of in situ melanoma that has a predilection for sun-exposed areas. LMs are commonly found on the head and neck,

Fig. 6. Superficial spreading melanoma.

comprising 10% to 26% of all melanomas occurring in this region [40,51 – 54]. LM subtypes are the most common variant of melanoma on the face, with the malar area an especially frequent site of involvement. Incidence is highest in older patients, with a mean age of 65 years at diagnosis [55,56]. Clinically, LMs appear as ill-defined, pigmented patches that are sometimes mottled with variegated color (Fig. 7). They are often found on skin that has underlying actinic damage. LMs grow slowly, frequently remaining as in situ lesions for years [6]. Approximately 5% to 33% of LMs will eventually invade the dermis, becoming lentigo maligna melanomas (LMM) [57]. LMMs comprise 4% to 15% of all melanoma cases (Fig. 8) [3,46,58 – 62]. Palpability of the lesion is a worrisome sign and might indicate transformation to an invasive malignancy. When a lentigo maligna becomes invasive (ie, LMM), the prognosis is similar to that of other invasive melanomas. Acral lentiginous melanoma

Fig. 5. Melanoma demonstrating variegated color with shades of pink and brown.

About 8% of melanomas are of the acral lentiginous subtype [6]. These lesions are most common in dark-skinned individuals and are relatively rare in

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survival rates between 15% and 20% [63,64]. This is most likely caused by a delay in diagnosis. Paranasal sinus lesions are uniformly fatal within 5 years, whereas nasal and oral lesions have 5-year survival rates of 30.9% and 12.3%, respectively [40].

Biopsy technique

Fig. 7. Lentigo maligna. Note the ill-defined nature.

Caucasians. They make up 60% to 72% of all melanomas in African Americans. Acral lentiginous melanomas typically appear on glabrous skin, in areas that are well protected from the sun and covered by thick epidermis. Soles and palms are the primary sites of involvement. Acral lentiginous melanomas can also be found on nail beds and oral and genital mucosal membranes. Clinically, these tumors appear to be similar to superficial spreading melanomas, with dark, variegated pigmentation and irregular margins. They sometimes have a benign appearance, mimicking callouses or warts.

Any lesion that is suspicious for melanoma should be biopsied for pathologic examination. Excisional biopsy of the lesion is the preferred technique because it provides the entire lesion for histopathologic review. Obtaining a sufficiently deep margin is imperative in determining the tumor’s Breslow depth, which guides treatment and portends prognosis. When an excisional biopsy is not feasible either because of tumor size or an unfavorable anatomic site, an incisional biopsy should be performed. Punch biopsy is a quick and simple means of obtaining a full-thickness specimen, but it is limited by its ‘‘sampling’’ nature and might not provide the true Breslow depth of the lesion. Shave biopsies should be avoided because they only collect the most superficial aspects of the skin and might be inadequate for proper diagnosis. A shave biopsy might transect the tumor and thus might not provide an accurate Breslow measurement. Likewise, electrosurgical procedures and fine needle aspiration are not recommended because they can interfere with tissue architecture, thus preventing accurate pathologic examination [45,65].

Staging Melanoma staging determines prognosis and directs treatment (Table 1). In 1998, the Melanoma

Mucosal melanoma Mucosal melanomas are quite rare, representing only 1% to 2% of all melanomas [26,40]. Mucosal melanomas can be located in the nose, paranasal sinuses, oral cavity, or nasopharynx. The clinical presentation is nonspecific and symptoms are typically indolent, so a high index of suspicion is required for timely diagnosis. Oral lesions are most often asymptomatic. Sinonasal melanomas can present with visual disturbances, nasal obstruction, pain, epistaxis, or facial deformity [40]. The prognosis for mucosal melanomas is particularly poor, with 5-year

Fig. 8. Lentigo maligna melanoma.

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Table 1 AJCC 2002 melanoma staging classifications Stage

Breslow depth +/

0 IA IB

In situ V 1.0 mm w/o ulceration & Clark’s level II/III V 1.0 mm w/ ulceration or Clark’s level IV/V 1.01 – 2.0 mm w/o ulceration 1.01 – 2.0 mm w/ ulceration 2.01 – 4.0 mm w/o ulceration 2.01 – 4.0 mm w/ ulceration > 4.0 mm w/o ulceration >4.0 mm w/ ulceration

IIA IIB IIC IIIA

ulceration

IIIB

IIIC

IV

T, N, or M classification TIS T1a N0 M0 T1b (w/ ulceration) N0 M0 T2a (w/o ulceration) N0 M0 T2b (w/ ulceration) N0 M0 T3a (w/o ulceration) N0 M0 T3b (w/ ulceration) N0 M0 T4a (w/o ulceration) N0 M0 T4b (w/ ulceration) N0 M0 Any T (except T4b if BD >4.0 mm, then cannot be ulcerated) & 1 (N1a) 3 (N2a) LNs + for microscopic disease only, M0 Any T (including T4b) & microscopic + 1 (N1a) 3 (N2a) LNs only Any T except T4b & macroscopic + for 1 (N1b) 3 (N2b) LNs Any T except T4b & neg LNs & + in-transit/satellite mets (N2c) M0 Any T & 1 (N1b) 3 (N2b) + LNs (macroscopic) Any T &  4 LNs, or matted LNs, or + in-transit/satellite mets (N3) M0 Any T, any N, any M M1a distant skin, SC or distant LN met, normal LDH M1b lung met, normal LDH M1c all other visceral mets & z LDH

Abbreviations: BD, Breslow depth; IS, in situ; LDH, serum lactate dehydrogenase level; LNs, lymph nodes; mets, metastases; neg, negative; SC, subcutaneous; w/, with; w/o, without; +, positve, z, elevated. From Rouse C, Allen A, Fosko S. Review of the 2002 AJCC Cutaneous Melanoma Staging System. Facial Plast Surg Clin N Am 2003;11:6.

Staging Committee met to redesign the staging system [66]. Breslow depth continues to be central in determining the correct stage. The most important change from prior versions is a new emphasis on tumor ulceration. In the newly proposed system, melanoma ulceration is associated with a worse prognosis; if it is present the patient is upstaged. Clark’s level is taken into account only in lesions that have a tumor thickness of 1 mm or less, and it is of greatest value in areas of thinner tissue levels such as the eyelid, ear, lip, and mucosal surfaces. New focus is also placed on the number of involved lymph nodes rather than on the size of the affected nodes. Finally, patients with intransit and satellite lesions are staged similarly to patients with regional nodal disease [48].

Treatment Surgical excision is the mainstay of melanoma treatment. Excision entails complete removal of the lesion through the subcutaneous fat to fascia, including an adjacent radius of normal-appearing skin.

Current surgical margin guidelines are the result of numerous trials ever since Breslow and Macht first suggested more conservative margins for thin tumors in 1977 [67,68]. These guidelines are based on the Breslow depth with the notion that deeper tumors carry a greater risk of local micrometastases and therefore warrant wider surgical margins [45]. The following guidelines are appropriate for most cutaneous melanomas. Melanomas in situ can be removed with 5-mm margins. Thin melanomas ( V1 mm) should be excised with a 1-cm margin. Intermediate tumors (1– 4 mm) require a 2-cm margin [69,70]. Thick tumors ( 4 mm) necessitate a 2- to 3-cm margin. Tumor ulceration can prevent accurate tumor thickness assessment, thus requiring larger surgical margins than those based on the lesion’s Breslow depth [45].

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Mohs’ micrographic surgery A unique treatment approach using Mohs’ micrographic surgery should be utilized when treating melanomas that have ill-defined clinical margins, in particular those of the LM subtype [45,55,71,72], which have a higher incidence of local recurrence compared with other in situ melanomas [73]. LMs frequently require wider surgical margins, often in an unpredictable direction. This is of particular concern when managing lesions in difficult anatomic locations such as the eyelids, nose, lips, or ears. Mohs’ surgery is a sequential, step-wise sectioning technique that uses histopathology to assess tumor margins in all dimensions [74]. The goal of Mohs’ surgery is the histopathologic evaluation of 100% of tumor margins, in contrast to less than 1% of surgical margins evaluated with standard excisional surgery and pathologic evaluation [65]. The use of the Mohs’ micrographic surgical approach has been shown to improve local tumor control, thereby significantly reducing the rate of recurrence [72]. It is a safe method that has the capacity to preserve cancerfree skin, thereby allowing optimal cosmetic and functional results [75 – 77]. While Mohs’ surgery is widely accepted and utilized in the treatment of LM and LMM, there is a debate among clinicians regarding which histopathologic tissue preparation modality (frozen sections versus paraffin sections) affords the greatest pathological and interpretative accuracy. Recently, some authors have asserted that using frozen sections alone makes identification of peripheral atypical melanocytes difficult [78,79]. These authors promote alternate methods such as paraffin-embedded sections and rush paraffin-embedded sections with or without immunoperoxidase staining [78,80 – 82]. Staged Mohs’ excisional approach In managing facial and scalp LM and LMM, a staged Mohs’ excisional approach can be helpful. The initial step is clearing the tumor’s peripheral margins, which might require multiple patient visits. When the margins are tumor-free, the remaining central portion of the lesion is excised. This step can be performed at the time of reconstruction. Vertical sections are taken to assess for an invasive component. The tissue is processed with vertical sections to aid in assessment of any invasive melanoma. The advantages of the staged approach are several fold. Foremost, the histopathologic tumor margins are assessed more accurately, thereby minimizing the risk of local recurrence. Additionally,

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this approach can reduce wound morbidity, which can occur while awaiting traditional staged surgical excision tissue margin assessment. The staged approach also eliminates the difficulty encountered when a positive margin is found after the wound is reconstructed [81]. Sentinel lymph node biopsy The role of sentinel lymph node biopsy is currently being investigated in the management of melanoma. This method utilizes lymphoscintigraphy to map out lymph node involvement, targeting lymph nodes closest to the cutaneous lesion. The sentinel lymph node is biopsied and examined microscopically. Based on the results, a more extensive lymph node dissection might be required. Sentinel lymph node biopsy is most commonly performed in melanomas that have a Breslow depth of greater than 1 mm [83]. Radiation therapy The role of radiation therapy as a primary treatment modality for melanoma remains controversial. The efficacy of radiation therapy is significantly lower than that of surgery; local recurrence rates approach 50% [84]. Radiation therapy is therefore reserved for patients who refuse surgery, are poor operative candidates, or in whom surgery would require extensive reconstruction. Interferon-a is a biologic therapy that is currently FDA-approved for the treatment of tumors with a Breslow depth of greater than 4 mm or for tumors with lymph node involvement. It appears to have the greatest effect in patients with lymph node disease. Interferon-a can be used alone or in combination with chemotherapy [74]. Chemotherapy is recommended as adjunctive treatment in patients with advanced disease. Dacarbazine is the only chemotherapeutic agent that is currently approved for treatment of metastatic melanoma. Response rates range from 10% to 20% and improvement is generally modest. Its use is typically limited to palliation in cases of metastatic or recurrent disease. Other treatments Because of the immunogenic nature of melanoma, it has been a prototype tumor for laboratory and clinical immunotherapy modalities [71]. Melanoma vaccines have made advancements over the past decade, and several clinical trials are currently under-

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way [40]. Many classes of vaccines are being studied including peptide, carbohydrate, antibody, and DNAbased vaccines. Phase II studies have shown some promise, but to date no Phase III trials have shown improvement in disease-free survival or a reduction in mortality [85]. Administration of bacillus Calmette-Guerin and other immunostimulants have thus far failed to improve outcome, so they are not part of standard melanoma treatment [77]. Because chemotherapy and immunotherapy results alone have proven to be unsatisfactory, current studies are combining these approaches. Initial trials showed higher response rates but similar survival rates and worse toxicity when compared with either therapy alone [86,87]. Current clinical trials are evaluating this method as an adjuvant therapy for systemic disease [40].

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Prevention [14]

Melanoma risk can be reduced by avoidance of harmful ultraviolet radiation. Patients should be advised to utilize protective clothing and hats and avoid sun exposure between the hours of 10:00 AM and 4:00 PM. When exposed to sunlight, liberal use of a broad-spectrum sunblock (sun protection factor 15 or higher) is recommended. Sunblock must be reapplied every 2 hours and after swimming. Use of tanning beds should be discouraged; topical ‘‘fake tan’’ creams can be suggested as a safe alternative. Skin self-examinations should be encouraged and patients should be educated about the appearance and behavior of melanoma and its precursors. Patients should seek prompt medical attention if suspicious lesions are identified.

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